Epilepsy is a central nervous system disorder characterized by the repeated occurrence of sudden and transitory episodes of abnormal phenomena of motor, convulsion, sensory, autonomic, or psychic origin. The disorder afflicts millions of people worldwide, and occurs more commonly in children than in adults.
Phenytoin (5,5-diphenyl-2,4-imidazolidinedione) and its alkali metal salts (e.g., sodium, lithium and potassium) represent antiepileptic drugs. The indication for phentyoin includes control of generalized tonic-clonic (grand mal) seizures and complex partial seizures (temporal lobe psychomotor). See, Pharmaceutical Sciences, Remington, 18th Ed., Mack Publishing Co. 1990, pp. 1078. The primary site of action for phenytoin appears to be the cerebral motor cortex where spread of seizure activity is inhibited.
Upon ingestion and exposure in the gastrointestinal pH range of 1 to 8, phenytoin sodium is converted to phenytoin which is practically insoluble because it is a relatively weak acid (pKa=8.3). Phenytoin's insolubility makes it difficult to deliver a dosage form of phenytoin which has a consistent dissolution profile over an extended period of time. The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5-7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. Because clinically significant toxicity can be encountered after administration of phenytoin, proper dosing is essential. Goodman & Gilman's, The Pharmacological Basis of Therapeutics, J. Harman et al. eds., pg. 468-469, 9th Edition, McGraw-Hill, New York, 1996. In order to control seizures while avoiding the side effects of the medication, phenytoin dosing requires optimization. Serum level determination is necessary for optimal dosage adjustments to maintain concentrations of phenytoin in the therapeutic range of 10 and 20 μg/mL. In general, the initial adult dosage of phenytoin is 100 mg three times daily. For most adults, a satisfactory maintenance dose will be 300 mg or 400 mg a day. Peak levels indicate an individual's threshold for dose-related side effects and are obtained at the time of expected peak concentration. Conventional dosage forms and their mode of operation, including dose peaks and valleys, are discussed in details in Pharmaceutical Sciences, Remington, 18th Ed., 1990, Mack Publishing Co. pp. 1676-1686; The Pharmaceutical and Clinical Pharmacokinetics, 3rd Ed., 1984, Lea and Febiger, Philadelphia, pp. 1-28; and in U.S. Pat. Nos. 3,598,122 and 3,598,123.
Phenytoin sodium is currently available in the U.S. in a number of different dosage forms. For example, dosage forms include an immediate release or “prompt” capsule, an extended release capsule, a chewable tablet, an oral suspension, and a parenteral solution. The “prompt” phenytoin sodium capsules exhibit a rapid rate of absorption with peak blood concentration in 1.5 to 3 hours. Because rapid release can lead to the development of undesirable toxic effects, the use of “prompt” phenytoin sodium is not recommended.
Several dosage systems have since been developed and marketed to provide an extended release dosage form and for reducing the number of daily administrations. For example, extended release formulations containing 30 and 100 mg phenytoin sodium are marketed by Warner-Lambert/Parke-Davis under the brand name Dilantin®. Dilantin® capsules contain 30 or 100 mg phenytoin sodium, lactose, confectioner's sugar, talc, and magnesium stearate as a loose powder and band sealed. In contrast to the “prompt” form of phenytoin sodium, the Dilantin® formulation exhibits a slower dissolution with prolonged absorption of the drug substance.
Other extended release formulations containing 200 and 300 mg phenytoin sodium are commercially available under the brand name Phenytek®. These extended release capsules contain 200 or 300 mg phenytoin sodium in an erodible matrix that includes povidone, hydroxyethyl cellulose, microcrystalline cellulose, magnesium oxide, colloidal silicon dioxide and magnesium stearate as disclosed in U.S. Pat. Nos. 6,274,168 and 6,620,432. The extended release capsules provide a peak serum level at 4 to 12 hours after administration.
Additional dosage forms exist and they involve enteric coating modifications in order to control the drug release. For example, U.S. Pat. No. 5,968,554 discloses a sustained release formulation containing phenytoin, a first enteric coating over the core, a second coating of the active ingredient, and a third coating that is soluble in gastric juices. U.S. Pat. No. 5,863,558 discloses a sustained release formulation containing a nonionic polymer that prevents the contact of phenytoin sodium with the gastrointestinal environment. This dosage form includes at least one exit in the inert wall surrounding the internal compartment and the wall maintains its integrity during the drug release.
U.S. patent application Ser. No. 11/199,169 discloses an extended release formulation containing phenytoin sodium and hydroxypropyl methyl cellulose; however, the manufacturing process in the application involves the use of methylene chloride and isopropyl alcohol. Methylene chloride is considered a Class 2 solvent by the United States Food and Drug Administration and its presence in any pharmaceutical product is strictly limited (www.fda.gov, Guidance for Industry, Q3C—Tables and List).
Other modes of antiepileptic drug administration include a nonrate-controlling, dose-dumping capsule, or a nonrate-controlling, dose-dumping tablet, and usually at multiple, repetitive dosing intervals. This prior-art mode of therapy leads to an initial high dose of drug in the blood, followed by a decreased dose of drug in the blood.
There is a continuing need for the development of pharmaceutical formulations of phenytoin sodium that provide for a controlled rate of release over an extended period of time.